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Schizophrenia Genetic Networks Identified; Connection to Autism Found

Schizophrenia Genetic Networks Identified; Connection to Autism Found

11/11/2012
Although schizophrenia is highly genetic in origin, the genes involved
in the disorder have been difficult to identify. In the past few years,
researchers have implicated several genes, but it is unclear how they
act to produce the disorder. A new study by researchers at Columbia
University Medical Center identifies affected gene networks and provides
insight into the molecular causes of the disease.

The paper was published today in the online edition of the journal Nature Neuroscience.

Using
an unbiased collection of hundreds of mutations associated with
schizophrenia, the Columbia researchers applied a sophisticated
computational approach to uncover hidden relationships among seemingly
unrelated genes. The analysis revealed that many of the genes mutated in
schizophrenia are organized into two main networks, which take part in a
few key processes, including axon guidance, synapse function, neuron
mobility, and chromosomal modification.

The study also uncovered
an intriguing connection between schizophrenia and autism. “If we hadn’t
known that these were two different diseases, and had put all the
mutations into a single analysis, it would have come up with very
similar networks,” said the study’s senior author, Dennis Vitkup, PhD,
associate professor in the Department of Biomedical Informatics, the
Center for Computational Biology and Bioinformatics, and the Columbia
Initiative in Systems Biology at Columbia University Medical Center. “It
shows how closely the autism and schizophrenia genetic networks are
intertwined,” he added.

Although it will take time to translate
the findings into practical treatments, the study provides insight into
the molecular causes of schizophrenia. It also suggests that mutations
associated with schizophrenia, autism, and probably many other
psychiatric disorders, are likely to converge on a set of interrelated
molecular processes.

Computer analysis uncovers genetic networks

To
discover potential connections among genes mutated in schizophrenia,
Dr. Vitkup and colleagues developed a computational approach, called
NETBAG+, to identify networks of genes likely to be responsible for the
same genetic phenotype. They then gathered the strongest mutations that
had been observed in schizophrenia by other researchers—including a set
of de novo mutations recently described by a team of Columbia
researchers led by Maria Karayiorgou, MD, and Joseph A. Gogos, MD,
PhD—and fed them into the program.

The program uncovered two
genetic networks. Genes in the first network are involved primarily in
axon guidance, synapse function, and cell migration. Genes in the second
network are involved in chromosomal organization and remodeling.

Parts
of both networks are highly active during prenatal development,
suggesting that changes in the brain that cause schizophrenia later in
life are laid down very early in life.

Connection to autism

Dr.
Vitkup also compared his schizophrenia networks with networks found in
neurodevelopmental disorders such as autism. One schizophrenia network
is strongly related to an autism network he described in a study
published last year. Both networks contain genes involved in axon
guidance, synapse function, and cell migration.

“Our recent
mutational analysis showed that this overlap includes primarily genes
that are important for early fetal development. This is not surprising,
because some cases of schizophrenia and likely many cases of autism have
neurodevelopmental origin,” said Dr. Karayiorgou.

The close
relationship between genetic networks involved in autism and
schizophrenia raises an intriguing question: How can mutations in the
same or related genes cause two different disorders?

“I like to
use the analogy of car brakes,” said Dr. Vitkup. “Different mechanical
malfunctions of the brake mechanism can have very different functional
consequences, from rapid acceleration to stalling.”

Dr. Vitkup
looked at large mutations called copy number variants (CNVs) that can
lead to either schizophrenia or autism. CNVs involve long stretches of
the genome containing several genes that have been either duplicated or
deleted. Duplication of a region increases the “dosage” of its genes;
deletion of a region decreases the dosage.

In CNVs involved in the
growth of dendrites, or dendritic spines, at the ends of neurons, he
found decrease in growth to be more common in schizophrenia and increase
in growth more common in autism. “That’s consistent with what’s been
found by postmortem brain studies,” he said.

“Evidence of
functional convergence among risk genes is consistent with the notion
that schizophrenia and autism are both primarily diseases of neuronal
communication. However, they have distinct clinical features and the
challenge remains to identify the critical neural circuits and
mechanisms that differentiate them,” said Dr. Joseph A. Gogos. “This is a
step in that direction.”

Dr. Vitkup predicts that many more genes
involved in schizophrenia and autism will eventually be found—possibly
up to 1000 genes for each disorder—but a significant fraction of them
will likely fall into the networks and pathways identified in the
current study.

“Until a few years ago, people were looking for
just a handful of genes responsible for autism and schizophrenia, so the
idea that many hundreds of genes are involved is a big change in
thinking,” Dr. Vitkup said. “Our study and the studies of our
collaborators suggest that in the search for the causes of complex
genetic disorders, it will be more productive to look for common
pathways and gene circuits than for a handful of causal genes. This type
of network analysis gives us a way to begin to make sense of what’s
happening.”

Study points way to future approaches to gene discovery

“To
uncover all of the processes and molecular pathways involved in
schizophrenia and related disorders, more gene searches are clearly
necessary,” said Dr. Vitkup.

Until recently, the hunt for disease
genes was focused primarily on analyses of common genetic mutations,
using so-called genome-wide association studies (GWAS). But according to
Drs. Vitkup, Karayiorgou, and Gogos, a complementary, possibly less
expensive, approach may be more fruitful. “By looking at individuals
with schizophrenia who are born into families with no history of the
disorder,” Dr. Vitkup said, “we can identify de novo mutations that are
likely to have caused their disorder.”

Drs. Karayiorgou and Gogos
recently used this approach to uncover many dozens of new schizophrenia
mutations from several hundred families; nearly every mutation was
unique to one patient.

“Our study demonstrates that through
network-based analyses of rare de novo mutations, it is possible to
implicate relevant molecular processes,” said Dr. Vitkup. “Applying
similar methods to larger cohorts of patients, we should be able to
delineate all of the pathways and molecular processes underlying complex
psychiatric disorders such as schizophrenia.”

The research makes sense to me - both disorders start long before birth, both are neurological, both have to do with how nerves function, but also with how they grow and develop long before birth. They are going to have a lot in common as far as what genes are involved.

MOST people will insist that's the ONLY connection, that the two disorders are entirely different, and I've heard many parents of autistic kids get infuriated if anyone suggests there is any relationship more than 'both are in the brain'. Most people have a horror of autism being called 'a kind of retardation' or 'a kind of mental illness'.

In fact, it's long been my feeling that neither mental retardation nor mental illness exist as categories; both are developmental, neurological disorders, as is autism.

I'd caution parents - there are going to be a lot more similarities than just that both are developmental and both are in the brain. Keep in mind that VERY small genetic differences can lead to VERY BIG differences in what we see in the end result. Yet those genes can be closely related.

Quoting trippyhippy:

Schizophrenia Genetic Networks Identified; Connection to Autism Found

11/11/2012 Although schizophrenia is highly genetic in origin, the genes involved in the disorder have been difficult to identify. In the past few years, researchers have implicated several genes, but it is unclear how they act to produce the disorder.

Not sure why anyone would claim the above - actually HUNDREDS of genes have been identified. But not all of the abnormalities to the genes are inherited - quite a few are quite small mutations - copy errors, they're called, and they've been difficult to detect til recently with new technology.

A new study by researchers at Columbia University Medical Center identifies affected gene networks and provides insight into the molecular causes of the disease.

Note he said GENE NETWORKS. They were studying areas of genes that affect each other. This is a fairly new area of study. What it means is that genes interact with, and regulate, each other.

This and epigenetics - how what is basically an 'uber gene' influences other genes, are becoming very, very important. An epigene is like a 'gene boss' and controls other genes.

Initially, this was studied in very simple one celled animals and gradually worked up to studying higher forms of life. It's becoming very important. It plays a big role in cells 'knowing' what they're supposed to do. It's going to be very important in disorders like autism and schizophrenia.

The paper was published today in the online edition of the journal Nature Neuroscience.

Using an unbiased collection of hundreds of mutations associated with schizophrenia, the Columbia researchers applied a sophisticated computational approach to uncover hidden relationships among seemingly unrelated genes. The analysis revealed that many of the genes mutated in schizophrenia are organized into two main networks, which take part in a few key processes, including axon guidance, synapse function, neuron mobility, and chromosomal modification.

The above functions relate not just to how nerve cells function daily, but how they begin to develop and grow in the fetus before birth. Not surprising - for quite some time, researchers have suspected genes that are responsible for those functions, were messed up in schizophrenia and other developmental disorders. This confirms their suspicions and narrows them down further.

Many researchers have slogged along for years, working from symptom to nerve cell to cell protein, to the gene that should produce that protein...this study took all the gene mutations found in a group of schizophrenics, and mapped which genes they occured in. Basically research worked from one direction inward for years (symptom to cell to protein) and now it's reaching back the other way - mutation to protein to cell. It's like when the first rail road in the US was completed - by building from the west to the east, and east to west, to meet at one point, and this is that point.

The study also uncovered an intriguing connection between schizophrenia and autism. “If we hadn’t known that these were two different diseases, and had put all the mutations into a single analysis, it would have come up with very similar networks,” said the study’s senior author, Dennis Vitkup, PhD, associate professor in the Department of Biomedical Informatics, the Center for Computational Biology and Bioinformatics, and the Columbia Initiative in Systems Biology at Columbia University Medical Center. “It shows how closely the autism and schizophrenia genetic networks are intertwined,” he added.

Yes, as I noted at the beginning of the article.

Although it will take time to translate the findings into practical treatments, the study provides insight into the molecular causes of schizophrenia. It also suggests that mutations associated with schizophrenia, autism, and probably many other psychiatric disorders, are likely to converge on a set of interrelated molecular processes.

Makes perfect sense to me.

Computer analysis uncovers genetic networks

To discover potential connections among genes mutated in schizophrenia, Dr. Vitkup and colleagues developed a computational approach, called NETBAG+, to identify networks of genes likely to be responsible for the same genetic phenotype. They then gathered the strongest mutations that had been observed in schizophrenia by other researchers—including a set of de novo mutations recently described by a team of Columbia researchers led by Maria Karayiorgou, MD, and Joseph A. Gogos, MD, PhD—and fed them into the program.

'de novo' means that the genetic mutation in an offspring, did not exist in the parents. 'De novo' means 'new'.

The program uncovered two genetic networks. Genes in the first network are involved primarily in axon guidance, synapse function, and cell migration. Genes in the second network are involved in chromosomal organization and remodeling.

Parts of both networks are highly active during prenatal development, suggesting that changes in the brain that cause schizophrenia later in life are laid down very early in life.

Quite long ago, some researchers were able to show that genetic changes that occur in utero are not always obvious right from birth. The 'core' symptoms associated with schizophrenia(hallucinations, delusions) don't usually start til young adulthood - so for a long time, some people assumed the CAUSE had to have occured in young adulthood, too. In other words, symptoms started in adulthood, so the cause must be rooted in adulthood. Woops! That was wrong. VERY wrong.

Connection to autism

Dr. Vitkup also compared his schizophrenia networks with networks found in neurodevelopmental disorders such as autism. One schizophrenia network is strongly related to an autism network he described in a study published last year. Both networks contain genes involved in axon guidance, synapse function, and cell migration.

Not at all a surprise. The normal human brain goes through some pretty astounding changes - brain cells actually migrate to their final position from several 'nursery' areas of the very early brain. They must then 'park' in the right spot, reach out and connect to other nerve cells.Then at key points of development, certain nerve cells are knocked out, and new connections are made - FEWER connections. It was long suspected this had gone wrong in many developmental disorders, particularly autism. It's long been known that autistic children's brains are often larger than normal...which suggests the brain growth has gone wrong.

“Our recent mutational analysis showed that this overlap includes primarily genes that are important for early fetal development. This is not surprising, because some cases of schizophrenia and likely many cases of autism have neurodevelopmental origin,” said Dr. Karayiorgou.

That's an odd thing to say...Most researchers would say that ALL cases of schizophrenia are neurodevelopmental. Psychosis (which is just one symptom of schizophrenia) can be caused by other things beside schizophrenia(alzheimers, drug use, kidney disease, lupus, depression, etc). This is like saying 'head ache' is a symptom of migraine, but can also be due to being whopped on the head by a football player.

The close relationship between genetic networks involved in autism and schizophrenia raises an intriguing question: How can mutations in the same or related genes cause two different disorders?

I've read some interesting articles on this over the years. One neurologist researcher made a very good point. When a series of events occur in the brain is just as important as WHAT exactly happens. You might compare it to being born blind, to losing vision at age 20. WHEN things happen is just as important as WHAT happens. But also, small differences in what happens can be very crucial.

“I like to use the analogy of car brakes,” said Dr. Vitkup. “Different mechanical malfunctions of the brake mechanism can have very different functional consequences, from rapid acceleration to stalling.”

Dr. Vitkup looked at large mutations called copy number variants (CNVs) that can lead to either schizophrenia or autism. CNVs involve long stretches of the genome containing several genes that have been either duplicated or deleted. Duplication of a region increases the “dosage” of its genes; deletion of a region decreases the dosage.

In CNVs involved in the growth of dendrites, or dendritic spines, at the ends of neurons, he found decrease in growth to be more common in schizophrenia and increase in growth more common in autism. “That’s consistent with what’s been found by postmortem brain studies,” he said.

So - same gene, different effect.

“Evidence of functional convergence among risk genes is consistent with the notion that schizophrenia and autism are both primarily diseases of neuronal communication. However, they have distinct clinical features and the challenge remains to identify the critical neural circuits and mechanisms that differentiate them,” said Dr. Joseph A. Gogos. “This is a step in that direction.”

Dr. Vitkup predicts that many more genes involved in schizophrenia and autism will eventually be found—possibly up to 1000 genes for each disorder—but a significant fraction of them will likely fall into the networks and pathways identified in the current study.

That makes perfect sense. Even a rookie like me agrees with that.

“Until a few years ago, people were looking for just a handful of genes responsible for autism and schizophrenia,

LOL! For years, guys like Irv Gottesman used to criticize every single gene study that failed to find ONE gene! LOL! He in particular complained about identical twin studies, but now they make absolute sense.

For a VERY long time, people, especially those not in genetics research, insisted there had to be one gene for schizophrenia OR ELSE(or else it was caused by bad toilet training or a ruined love affair, I suppose)!

They totally ignored the other possibility: that it is caused by MANY genes.

It just doesn't act like a one -gene disease. For one thing, most cases are mild or moderate - there are far fewer severe cases. For another,even two schizophrenic parents don't have all schizophrenic offspring. And for another, even identical twins don't both always get schizophrenia when one has it.

And interestingly, even if you take away a schizophrenic mother's child at birth, and raise it in a family of non schizophrenics, schizophrenia still occurs at the exact same rate as it occurs if the schizophrenic mother raises the child. That fact alone should have made people VERY suspicious of this 'multifactorial model', and that information has existed since the very early 1920's.

For years and years, many people were sure we were looking at the outcome of multiple genes. Epidemiologists have been pointing that out, over and over, for years. That schizophrenia 'occurs like a 'cloud'' of genes cause it, not like one gene at all.

so the idea that many hundreds of genes are involved is a big change in thinking,” Dr. Vitkup said.

Not for me or the many researchers I've been following. This is just additional proof.

“Our study and the studies of our collaborators suggest that in the search for the causes of complex genetic disorders, it will be more productive to look for common pathways and gene circuits than for a handful of causal genes. This type of network analysis gives us a way to begin to make sense of what’s happening.”

Yes, this has been the thinking on schizophrenia among researchers for a long time.

Study points way to future approaches to gene discovery

“To uncover all of the processes and molecular pathways involved in schizophrenia and related disorders, more gene searches are clearly necessary,” said Dr. Vitkup.

We can easily get to where we have a vaccine(gene therapy) against schizophrenia, autism, bipolar, etc. Maybe not before I die, but it is my dream that I live long enough to see that day. Even if a vaccine could reduce its severity, or cut down the number of cases.

Until recently, the hunt for disease genes was focused primarily on analyses of common genetic mutations, using so-called genome-wide association studies (GWAS). But according to Drs. Vitkup, Karayiorgou, and Gogos, a complementary, possibly less expensive, approach may be more fruitful. “By looking at individuals with schizophrenia who are born into families with no history of the disorder,” Dr. Vitkup said, “we can identify de novo mutations that are likely to have caused their disorder.”

This is the way to find de novo mutations. And some researchers feel that within a few years, we will have confirmation that 100% of the risk of schizophrenia is from these de novo mutations.

Drs. Karayiorgou and Gogos recently used this approach to uncover many dozens of new schizophrenia mutations from several hundred families; nearly every mutation was unique to one patient.

The genetic mutations themselves were unique, but again, most of these are still going to be occuring within their network.

“Our study demonstrates that through network-based analyses of rare de novo mutations, it is possible to implicate relevant molecular processes,” said Dr. Vitkup. “Applying similar methods to larger cohorts of patients, we should be able to delineate all of the pathways and molecular processes underlying complex psychiatric disorders such as schizophrenia.”

It's really quite brilliant to go at it this way. It really is a fast track to better treatments.

I hope those people are VERY happy because this is great work that they did. I know it's hard for many people to understand what they did, but it is huge. It confirms what many have suspected for years, more and more strongly as the evidence accumulated.

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